Review Article
Association between Systemic Diseases and
Endodontic Outcome: A Systematic Review
Anita Aminoshariae, DDS, MS,* James C. Kulild, DDS, MS,* Andre Mickel, DDS, MSD,*
and Ashraf F. Fouad, DDS, MS†
Abstract
Introduction: To date, the relationships between sys-
temic diseases and endodontic treatment outcomes
remain poorly studied. Thus, the purpose of this system-
atic review was to evaluate the relationship between
host-modifying factors and their association with
endodontic outcomes. Methods: Two reviewers inde-
pendently conducted a comprehensive literature search.
The MEDLINE, Embase, Cochrane, and PubMed
databases were searched. In addition, the bibliographies
and gray literature of all relevant articles and textbooks
were manually searched. There was no disagreement
between the 2 reviewers. Results: Sixteen articles met
the inclusion criteria with moderate to high risk of
bias. There was no article with low risk of bias.
Available scientific evidence remains inconclusive as to
whether diabetes and/or cardiovascular disease(s) may
be associated with endodontic outcomes. Human immu-
nodeficiency virus and oral bisphosphonate did not
appear to be associated with endodontic outcomes.
Conclusions: Although additional well-designed longi-
tudinal clinical studies are needed, the results of this
systematic review suggest that some systemic diseases
may be correlated with endodontic outcomes. (J Endod
2016;-:1–6)
Key Words
Cardiovascular disease, diabetes, endodontic outcome,
human immunodeficiency virus, hypertension, medical
conditions, systemic disease
From the *Department of Endodontics, School of Dental Medicine, Case Western Reserve University, Cleveland, Ohio; and †Department of Endodontics, School of
Dentistry, University of North Carolina, Chapel Hill, North Carolina.
Address requests for reprints to Dr Anita Aminoshariae, 2123 Abington Road A 280, Cleveland, Ohio 44106. E-mail address: aaminoshariae@yahoo.com
0099-2399/$ - see front matter
Copyright ª 2016 American Association of Endodontists.
http://dx.doi.org/10.1016/j.joen.2016.11.008
JOE — Volume -, Number -, - 2016
S ystemic diseases and
oral infections are
closely related because
Significance
Although additional well-designed clinical studies
are needed, the results of this systematic review
they both share many
suggest that some systemic diseases may influ-
associated risk factors
ence endodontic healing outcomes.
(1–3). In a previous
systematic review, our
group reported that there may be a correlation between some systemic diseases and
the pathogenesis of endodontic diseases (4). However, there is also a need to address
the relationship of systemic diseases and endodontic treatment outcomes because this
provides valuable information on the prognosis of endodontic treatment.
Several systemic diseases were found to be correlated with the outcome of
endodontic treatment. Diabetes mellitus was reported to be significantly associated
with reduced endodontic healing treatment outcomes of teeth with preoperative infec-
tions, suggesting that diabetes may serve as a disease modifier (5, 6). Also, both diabetes
and hypertension were found to be significantly associated with reduced survival of
endodontically treated teeth (7). Therefore, systemic conditions and disorders may
have an influence in the healing outcome of endodontically treated teeth rather than
just acting as a causative etiologic factor in endodontic infections (1, 8, 9).
To date, the relationship of systemic medical conditions and outcomes of
endodontic treatment remains poorly studied. Therefore, the purpose of this systematic
review was to evaluate the relationship between systemic diseases and outcomes in end-
odontic treatment.
Materials and Methods
The protocol for this systematic review was developed following established guide-
lines (10). The protocol was prepared and registered on PROSPERO (registration num-
ber: CRD42016042711). Also, a well-defined review question was developed by using
the patient population, intervention, comparison, and outcome (PICO) framework.
The Cochrane Collaboration’s tool for assessing risk of bias, the Oxford Systematic
Review Appraisal Sheet, and Critical Appraisal Skills Programme were used to ensure
the accuracy of this data analysis in this systematic review (10–12).
Formulating the Review Question
The following PICO framework was developed for a systematic review of the
existing literature regarding apical pathosis and systemic diseases. When compared
with medically healthy individuals, can systemic diseases influence endodontic clinical
and radiographic healing outcomes?
Systemic Diseases and Endodontic Outcome 1
Review Article
Inclusion and Exclusion Criteria
1. The following types of studies were considered: clinical trials, case-
control studies, cross-sectional studies, or cohort studies published
in English language peer-reviewed scientific journals from 1997
to 2016.
2. The study must have had a control group.
3. The effect of systemic diseases on healing outcomes was measured.
4. Studies in which the healing outcome was defined in terms of
clinical/radiographic healing and/or survival of the tooth.
Exclusion criteria included the following: the type of study: case
series, cell culture laboratory studies, or animal studies.
Search Methodology
The electronic MEDLINE, Embase, Cochrane, and PubMed
databases were searched. In addition, the bibliographies of all relevant
articles and textbooks were manually searched. On the basis of inclu-
sion and exclusion criteria, 2 reviewers (A.A., J.K.) independently
selected the relevant articles.
To answer the clinically relevant question, a 4-step method of
evidence-based analysis was applied: step 1, a search for the clinical
evidence regarding the systemic diseases and biological markers in
electronic databases, and bibliographies of all relevant articles and
review articles were both electronically and hand searched; step 2,
appraisal and selection of articles according to study validity and clinical
importance; step 3, collection and analysis of the published evidence;
and step 4, determining the clinical applicability of the results.
By using the PICO formatted question, methodological MeSH
(medical subject heading) terms were generated to make the search
strategy more sensitive in identification of studies. These terms included
endodontics, systemic disease and apical periodontitis, diabetes, hyper-
tension, cardiovascular disease, endodontic and medical condition,
apical periodontitis, and endodontic outcome. Studies that met the
above inclusion criteria underwent critical analysis.
Extracted data included the size of the population in the group(s);
the number of dropouts or withdrawals, if reported; a description of the
materials and methods with a detailed assessment of systemic diseases;
and the outcome variables used to measure the effect of biologic
markers on apical periodontitis.
The qualities of the included studies were evaluated according to a
proposed specific quality assessment scale.
Outcome Variables and Statistical Analysis
Because of the heterogeneity among the different study designs and
data from different systemic conditions, it was not possible to perform a
meta-analysis.
Results
Figure 1 presents a flowchart of the systematic review process
according to the Preferred Reporting Items for Systematic Reviews
and Meta-Analyses (PRISMA) guidelines (10). Sixteen articles met
the inclusion criteria for this systematic review. The overall quality of
the included articles was moderate to high risk of bias. Three articles
were identified to report on cardiovascular disease (CVD) (7, 13, 14).
Eleven articles reported on diabetes mellitus (DM) (6, 7, 13–21).
Three articles reported on human immunodeficiency virus (HIV)
(22–24). One article reported on oral bisphosphonate and
osteonecrosis of the jaw (25).
2 Aminoshariae et al.
Discussion
This systematic review focused on any associations between end-
odontic outcome and 4 systemic diseases (CVD, DM, HIV, and oral
bisphosphonate). The overall quality of the articles was determined to
have moderate to high risk of bias, which indicates the true effect is likely
to be close or substantially different from the estimate of the effect (26).
CVD
Both CVD and endodontic infections share similar inflammatory
mediators in the initiation and progression of the disease process
(27–29). Three articles were identified to address a relationship
between CVD and endodontic outcomes (7, 13, 14). Two had
moderate risk of bias (13, 14), and one had high risk of bias (7).
Two of these articles reported that there was a relationship, whereas
Ng et al (13) reported that there was no relationship between CVD
and outcomes of endodontic treatment.
DM
After an inflammatory reaction, elevated levels of circulating inter-
leukin 6 and tumor necrosis factor-a may impair glycemic control
(30). Six articles with moderate to high risk of bias reported that there
was an association between DM and endodontic outcomes (7, 9, 13–15,
18). Most of these articles had high risk of bias except two (13, 18),
which had moderate risk of bias.
Five articles with moderate to high risk of bias reported that there is
no association between DM and endodontic outcome (16, 17, 19–21).
All 5 articles demonstrated a high risk of bias except 1 article, which had
a moderate risk of bias (21).
Oral Bisphosphonates
Bisphosphonates inhibit osteoclast formation and activity and
shorten the life span of osteoclasts (31). However, current evidence
suggests that the possibility of developing osteonecrosis of the jaw after
oral bisphosphonate treatment is 1 in 23 patients or approximately 4%
of the population (32). Bone remodeling is an integral part of the heal-
ing process. Only 1 article with 7-month follow-up was identified to
address the effect of oral bisphosphonates and healing of nonsurgical
root canal therapy with periapical lesions (25). The article suggested
no association between oral bisphosphonate and endodontic outcomes.
The quality of the evidence was determined to be moderate. Thus, more
research is indicated in this area to clarify any current association.
HIV
Three parameters define the clinical staging for HIV: opportunistic
infections, CD4+ count, and viral load (33). T cells play an important
role in the development, progression, and resolution of endodontic
infections (34). The results of the current investigation identified 3
articles. Two articles had high risk of bias (22, 23) and one with
moderate risk of bias (24). All 3 articles suggested that there is no
correlation between HIV and outcomes of endodontic healing.
The results of the current systematic review also agree with other
studies, although they exhibit lower level evidence (33, 35, 36). Most of
the available studies that explored the relationship between endodontic
outcomes and systemic disease did not differentiate between cases with
preoperative infections and those with vital pulp. Clearly, when it comes
to endodontic prognosis, the single most important factor is the
presence of a preoperative lesion, a finding that was also true in the
studies reviewed here, which took this into consideration (6, 13).
In cases with vital pulp, the prognosis of endodontic treatment is very
good; therefore, the potential role of systemic disease may be
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Figure 1. Prisma 2009 flow diagram.
marginal and one that requires adequate controls to assess accurately.
However, cases with preoperative lesions have a significantly lower
prognosis, and the role of the systemic disease may be more
substantial. In this regard the study by Fouad and Burleson (6) found
no effect for DM on the entire population of treated patients during their
6-year evaluation period. However, when only the cases with preoper-
ative lesions were considered, a significant association was detected,
which became even more significant after a number of confounding var-
iables were controlled through a multivariate analysis. Future studies
should explore the difference in the prognosis of vital cases and cases
with infections separately, because infections remain the major clinical
problem in endodontic treatment.
Controlling for confounding variables is another important
requirement in studies evaluating oral and systemic diseases. Further-
more, because there is already a large body of evidence present on
the relationship of periodontal disease and systemic disease and on
the relationship of endodontic and periodontal prognosis, periodontal
disease should be added to the list of variables to be controlled. Many of
the reviewed studies controlled for these confounding variables
JOE — Volume -, Number -, - 2016
Review Article
(Table 1). This level of evidence allows the determination of whether
the systemic disease exerts an independent effect on endodontic treat-
ment outcomes.
A recent publication (37) reported that patients with medical con-
ditions (clustering all medically compromised patients in one group)
were not associated with poorer healing outcome after nonsurgical
root canal therapy. It should be noted that all medical conditions are
not the same. Also, in that study the severity of these medical conditions
was not discussed. Last, the information regarding the glycemic control,
complete blood count with differentials was not available to compare
(between the patients or even within the same patient) and then to
discern whether such association existed.
Thus, from this systematic review it remains inconclusive whether
there is or is not a relationship between CVD, DM, and endodontic out-
comes. Longitudinal investigations with well-designed research meth-
odologies are needed to address this question.
Although additional well-designed clinical studies are needed, the
results of this systematic review suggest that some systemic diseases may
influence endodontic healing outcomes.
Systemic Diseases and Endodontic Outcome 3
 TABLE 1. Characteristics of Studies Assessing the Relationship between Systemic Diseases and Endodontic Outcome
4

Review Article
Type of Endodontic
Aminoshariae et al.

Study disease Study design outcome Sample size Matching Main result Selection bias Detection bias Reporting bias Bias risk
Mindiola et al, Diabetes, Observational Survival 5460 cases No DM, hypertension, High High (unclear if teeth High (multivariate High
2006 (7) hypertension, cohort and CVD were were fractured, or analysis was not
CVD significant how instrumented performed to adjust
risk for tooth and/or other for age, tooth type,
extraction reasons that could final restoration for
contribute to final analysis
treatment failure) because they were
both reported
to be risk factors)
Wang et al, DM, CVD Cross-sectional Survival 49,334 patients, No Increased risk of Low (random) Low (all extracted Low (multivariate Moderate
2011 (14) 1592 teeth tooth extraction for teeth were analysis adjusted for
extracted NSRCT with DM, retrieved by age, tooth type for
during 2 y hypertension, CVD databank for final analysis
specific treatment because they were
codes and analyzed; both reported
technical failures to be risk factors)
were excluded)
Britto et al, DM Cross-sectional Radiographic 30 DM/23 control Yes Men with type High High (cross-sectional High (radiographic High
2003 (15) 2 diabetes who and radiographic only)
had NSRCT were evaluation only)
more likely to have
residual lesion
Fouad and DM Retrospective Radiographic 72 DM/459 control No Patients with DM High (information Low (radiographic High (multivariate High
Burleson, cohort 2 y and have reduced on patients’ degree and clinical exam) analysis was not
2003 (6) longer likelihood of of glycemic control performed).
endodontic success not available) Pulpal diagnosis,
in cases with severity of DM
preoperative lesions not discussed
Segura-Egea DM Cross-sectional Radiographic 32 DM/38 control No DM and Low High (radiographic High (radiographic High
et al, 2005 (17) endodontically only) only and cross-
treated teeth were sectional study)
not associated
(P = .17)
Doyle et al, DM and Retrospective Radiographic 196 implant/ Yes DM and NSRCT were High (information on Low High (multivariate High
2007 (16) smokers observational and clinical 196 NSRCT not associated. patients’ degree of analysis was not
cohort data Smoking was glycemic control or performed).
associated with what is defined by Pulpal diagnosis,
poorer outcome for smoking not severity of DM
both implants available) not discussed
and NSRCT
Lopez-Lopez DM Cross-sectional Radiographic 50 DM/50 control Yes Periapical status and Low (patients were High (radiographic Low (multivariate Moderate
et al, 2011 (18) case-controlled using periapical number of NSRCT randomly selected; only and cross- analysis adjusted for
index score were significantly DM classification sectional) confounding
associated with was defined) variables)
diabetic status
Ng et al, DM and Prospective Survival 572 patients No DM and steroids Low Low High (multivariate Moderate
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2011 (13) steroids and longitudinal (22 teeth DM/737 significantly analysis adjusted for
CVD study (4 y) normal teeth; influenced confounding
11 teeth steroids/ tooth survival for variables), but had
748 teeth normal; primary and low sample
58 teeth CVD; secondary size and evaluated
701 normal teeth) NSRCT. CVD was teeth not patients;
not found to multiple teeth were
influence used from the
NSRCT outcome same patient(s),
which in this
sample size
would affect the
outcome
JOE — Volume -, Number -, - 2016

Marotta DM Cross-sectional Radiographic 30 DM/60 control Yes No statistically High (non-random, High (radiographic High (did not adjust for High
et al, 2012 (19) case-controlled using full-mouth significant DM not described) only and cross- confounding
periapical and difference between sectional) variables)
panoramic NSRCT of control
radiographs and DM
Marques- DM Case-controlled Periapical and 23 DM/23 control No No statistically High (non-random, High (radiographic High (did not adjust for High
Ferreira panoramic r significant difference DM not described) only and cross- confounding
et al, 2014 (20) adiographs (P = .06) between sectional) variables)
NSRCT of control
and DM
Sanchez- DM Cross-sectional Radiographic 59 DM > 6.5 Yes No statistically Low High (radiographic Low (multivariate Moderate
Dominguez case-controlled hemoglobin significant only and cross- analysis adjusted
et al, 2015 (21) A1c/24 DM < 6.5 difference and sectional) for confounding
hemoglobin A1c glycemic control, variables)
CVD, smoking,
number of teeth,
and outcome of
root-filled teeth
Quesnell HIV Cohort (1 y) Radiographic 33 HIV/33 healthy No There were no High (patients were High (radiographic High (did not adjust High
et al, 2005 (22) using periapical statistically not matched for evaluation only) for confounding
index significant tooth type, variables)
differences preoperative
between the 2 with diagnosis, age,
respect to degree of gender, steroids,
periradicular antibiotics,
healing. smoking, CVD, etc)
Alley et al, HIV Cohort study (3 y) Radiographic 31 patients Yes No statistically High (non-random) High (radiographic Low High
2008 (23) chart review (50 teeth) HIV/ significant difference evaluation only and
46 patients between groups. evaluators were
(50 teeth) control not blinded)
Tootla and Owen, HIV Cohort study Radiographic 46 HIV/59 Yes No statistically High (non-random) Low Low Moderate
2012 (24) (6, 12, 18, and clinical control significant
24 mo) difference between
groups.
Hsiao et al, Bisphosphonate Retrospective Radiographic 34 oral Yes No statistically Low Low High (short Moderate
2009 (25) cohort (7-mo and clinical bisphosphonate/ significant follow-up)
follow-up) 38 control difference between
groups.

NSRCT, nonsurgical root canal treatment; PAI, periapical index score.

Systemic Diseases and Endodontic Outcome

Review Article
5
Review Article
Acknowledgments
The authors deny any conflicts of interest related to this study.
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